This invention relates to 2-phenylindoles, a process for their production, pharmaceutical preparations that contain the latter as well as their use for the production of pharmaceutical agents.
The new 2-phenylindoles are reproduced by general formula I 
in which
R1 means one of the radicals xe2x80x94(CH2)nxe2x80x94S(O)mxe2x80x94R4, xe2x80x94(CH2)nxe2x80x94NR6xe2x80x94SO2xe2x80x94R4, xe2x80x94(CH2)mxe2x80x2
whereby n and nxe2x80x2 are integers from 4 to 12 and m and mxe2x80x2 are 0, 1 or 2, and X stands for a methylene group, an imino group xe2x95x90NR6, an oxygen or sulfur atom,
R2 and R3, independently of one another, mean a hydrogen atom, a C1 to C10 alkyl group, a benzyl, alkanoyl or alkanoyloxy or carbamoyl radical of formula xe2x80x94C(O)R5 or xe2x80x94C(O)NR6R7 or a tetrahydropyranyl group,
R4 means a hydrogen atom, a C1 to C10 alkyl group, a completely or partially fluorinated alkyl group xe2x80x94(CH2)oxe2x80x94(CF2)pCF3, whereby o and p, independently of one another, are in each case an integer from 0 to 6, an (alkyl)amino or (alkyl)carbamoyl group of formula xe2x80x94(CH2)qxe2x80x94Yxe2x80x94NR8R9, whereby q is an integer from 0 to 6 and Y stands for a direct bond, a methylene or carbonyl group, but if Y means a carbonyl group and m is 2, q cannot be 0, an aryl, aralkyl or heteroaryl radical,
R5 means a C1 to C10 alkyl or C1 to C10 alkyloxy group, a phenyl or benzyl radical,
R6, R7, R8 and R9, independently of one another, mean a hydrogen atom, a C1 to C10 alkyl or benzyl group, and R10 means a methyl group and R11 means a hydrogen atom or R10 and R11 together mean a di-, tri- or tetramethylene bridge, which also can have a Cxe2x80x94C double bond anywhere in the bridge.
As alkyl groups with 1 to 10 carbon atoms for radicals R2, R3, R4, R5, R6, R7, R8 and R9, the radicals methyl, ethyl, propyl, butyl, pentyl, hexyl, hepty, octyl, nonyl and decanyl and also their branched-chain variants, for example the isopropyl, isobutyl or tert-butyl radicals, are suitable. Cycloalkyl groups with 3 to 10 carbon atoms, and among them especially the cyclopentyl or cyclohexyl radical, can also be mentioned.
A phenyl, 1- or 2-naphthyl radical can stand for an aryl radical R4; primarily a benzyl radical, but also a phenethyl, 1- or 2-naphthylmethyl radical can stand for an aralkyl radical R4; and mainly a 2-, 3- or 4-pyridinyl radical or an imidazolyl radical, which can carry a low alkyl group (C1-C4), for example a methyl group, but also a 2-pyrazine, 2-, 4- or 5-pyrimidine, 3-pyrazine as well as a 2- or 3-thiophene radical on the nitrogen atom can stand for a heteraryl radical R4.
If R5 is to be a C1-C10 alkoxy radical, this is primarily a methoxy, ethoxy, n- or isopropoxy, n-, iso- or tert-butoxy radical.
n or nxe2x80x2 preferably stands for an integer from 6 to 12, m can be 0, 1 or 2, all indicated meanings are equally possible for o and p; the combinations o=3 and p=1 as well as o=0 and p=0 are to be emphasized for the partially fluorinated alkyl radical R4; finally, q is preferably selected from the range of 2 to 5.
Radicals R2 and R3 preferably each represent a hydrogen atom.
The meanings of n, nxe2x80x2, m, mxe2x80x2, R4 with o, p, q, Y, R8 and R9 and R6 are selected together such that R1 preferably forms one of the following side chains:
xe2x80x94(CH2)10xe2x80x94Sxe2x80x94(CH2)4CH3 
xe2x80x94(CH2)10xe2x80x94SOxe2x80x94(CH2)4CH3 
xe2x80x94(CH2)10xe2x80x94SO2xe2x80x94CH24CH3 
xe2x80x94(CH2)12xe2x80x94SOxe2x80x94CH2)2CH3 
xe2x80x94(CH2)12xe2x80x94SO2CH2)2CH3 
xe2x80x94(CH2)8xe2x80x94Sxe2x80x94(2-Pyridinyl)
xe2x80x94(CH2)10xe2x80x94Sxe2x80x94[2-(N-Methyl)imidazolyl]
xe2x80x94(CH2)11xe2x80x94N(xe2x80x94CH3)xe2x80x94SO2xe2x80x94(CH2)2CH3 
xe2x80x94(CH2)11xe2x80x94N(xe2x80x94CH3)xe2x80x94SO2xe2x80x94CH2-Phenyl
xe2x80x94(CH2)10xe2x80x94SO2xe2x80x94N(xe2x80x94CH3)xe2x80x94(CH2)3CH3 
xe2x80x94(CH2)9xe2x80x94SOxe2x80x94(CH2)3C2F5 
xe2x80x94(CH2)9xe2x80x94SO2xe2x80x94CH2)3C2F5 
xe2x80x94(CH2)10xe2x80x94Sxe2x80x94CH2xe2x80x94COxe2x80x94N(xe2x80x94CH3)xe2x80x94CH(CH3)2 
xe2x80x94CH2xe2x80x94pxe2x80x94C6H4xe2x80x94Oxe2x80x94(CH2)4xe2x80x94SO2xe2x80x94C5H11 
xe2x80x94(CH2)6xe2x80x94Sxe2x80x94(CH2)xe2x80x94COxe2x80x94N(xe2x80x94CH3)xe2x80x94(CH2)3CH3 
Radical xe2x80x94OR2 can be present in the 4-, 5-, 6- or 7-position of the bicyclic compound of the phenylindole (benzo[a]carbazole).
Especially preferred are those compounds of general formula I in which radical xe2x80x94OR2 is bound to carbon atom 5.
The compounds that are mentioned below are preferred within the scope of this invention:
5-hydroxy-2-(4-hydroxyphenyl)-3-methyl-1-[10-(pentylthio)-decyl]-indole
5-hydroxy-2-(4-hydroxyphenyl)-3-methyl-1-[10-(pentylsulfonyl)-decyl]-indole
5-hydroxy-2-(4-hydroxyphenyl)-3-methyl-1-[12-(propylsulfonyl)-dodecyl]-indole
5-hydroxy-2-(4-hydroxyphenyl)-3-methyl-1-[9-(4,4,5,5,5-pentafluoropentylsulfonyl)-nonyl]-indole
5-hydroxy-2-(4-hydroxyphenyl)-3-methyl-1-[8-(2-pyridinylthio)-octyl]-indole
1-[10-(n-butyl-methylsulfamoyl)-decyl]-5-hydroxy-(4-hydroxyphenyl)-3-methylindole
5-hydroxy-2-(4-hydroxyphenyl)-3-methyl-1-[11-(N-methyl-propylsulfonamido)-undecyl]-indole
5-hydroxy-2-(4-hydroxyphenyl)-3-methyl-1-[11-(N-methyl-phenylmethanesulfonamido)-undecyl]-indole
1-{6-[3xe2x80x2-(n-butyl-methylcarbamoyl)-propylthio]-hexyl}-5-hydroxy-2-(4-hydroxyphenyl)-3-methylindole
5-hydroxy-2-(4-hydroxyphenyl)-3-methyl-1-[10-(pentylsulfinyl)-decyl)-indole
5-hydroxy-2-(4-hydroxyphenyl)-3-methyl-1-[9-(4,4,5,5,5-pentafluoropentylsulfinyl)-nonyl]-indole
6,11-dihydro-3,8-dihydroxy-5H-1-[10-(pentylthio)-decyl]benzo[a]carbazole
6,11-dihydro-3,8-dimethoxy-5H-1-[10-(pentylsulfonyl)-decyl]benzo[a]carbazole
5-methoxy-2-(4-methoxyphenyl)-3-methyl-1-[10-(pentylthio)-decyl]-indole
5-methoxy-2-(4-methoxyphenyl)-3-methyl-1-[10-(pentylsulfonyl)-decyl]-indole
5-methoxy-2-(4-methoxyphenyl)-3-methyl-1-[12-(propylsulfonyl)-dodecyl]-indole
5-methoxy-2-(4-methoxyphenyl)-3-methyl-1-[9-(4,4,5,5,5-pentafluoropentylsulfinyl)-nonyl]-indole
1-[10-(n-butyl-methylsulfamoyl)-decyl]-5-methoxy-2-(4-methoxyphenyl)-3-methylindole
5-methoxy-2-(4-methoxyphenyl)-3-methyl-1-[8-(2-pyridinylthio)-octyl]-indole
5-methoxy-2-(4-methoxyphenyl)-3-methyl-1-[11-(N-methyl-propylsulfonamido)-undecyl]-indole
5-methoxy-2-(4-methoxyphenyl)-3-methyl-1-[11-(N-methyl-phenylmethanesulfonamido)-undecyl]-indole
1-(6-mercaptohexyl)-5-methoxy-2-(4-methoxyphenyl)-3-methylindole
1-{6-[3xe2x80x2-(n-butyl-methylcarbamoyl)-propylthio]-hexyl}-5-methoxy-2-(4-methoxy-phenyl)-3-methylindole
5-hydroxy-2-(4-hydroxyphenyl)-3-methyl-1-[12-(propylsulfinyl)-dodecyl]-indole
6,11-dihydro-3,8-dimethoxy-5H-1-[10-(pentylthio)-decyl]benzo[a]carbazole
6,11-dihydro-3,8-dimethoxy-5H-1-[10-(pentylsulfonyl)-decyl]benzo[a]carbazole
5-hydroxy-2-(4-hydroxyphenyl)-3-methyl-1-[12-[2-(N-methyl-imidazolyl)thio]-decyl]-indole
5-hydroxy-2-(4-hydroxyphenyl)-3-methyl-1-[10-[(methyl-iso-propylcarbamoyl)-methylthio]-decyl]-indole
6,11-dihydro-3,8-dihydroxy-5H-1-[10-(pentylsulfinyl]-decyl]benzo[a]carbazole
6,11-dihydro-3,8-dihydroxy-5H-1-[9-(4,4,5,5,5-pentafluoropentylsulfinyl)-nonyl]benzo[a]carbazole
6,11-dihydro-3,8-dihydroxy-5H-1-[9-(4,4,5,5,5-pentafluoropentylsulfonyl)-nonyl]benzo[a]carbazole
6,11-dihydro-3,8-dihydroxy-5H-1-[10-(pentylmethylsulfamoyl)-decyl]benzo[a]carbazole
6,11-dihydro-3,8-dihydroxy-5H-1-[10-[2-(N-methyl-imidazolyl)thio]-decyl]benzo[a]carbazole
5-hydroxy-2-(4-hydroxyphenyl)-3-methyl-1-[4-[4-(pentylsulfonyl)butoxy]-phenyl]-indole
5-hydroxy-2-(4-hydroxyphenyl)-3-methyl-1-[4-[4-(pentylsulfonyl)butoxy]-benzyl]-indole
5-hydroxy-2-(4-hydroxyphenyl)-3-methyl-1-[4-[4-(pentylsulfonyl)butyl]methylamino]-phenyl]-indole
Especially to be emphasized within the scope of this invention are those compounds of general formula I, in which R10 together with R11 stand for an ethano or etheno bridge. For these compounds, the radicals R1 that are already mentioned above also are regarded as preferred.
It has been found that the compounds of general formula I according to the invention have strong antiestrogenic properties (competitive antiestrogens). Compounds with antiestrogenic properties, i.e., substances with inhibiting actions compared to estrogens, were already described in the literature.
As antiestrogens, for example, tamoxifen can be cited (Eur. J. Cancer Clin. Oncol. 1985, 21, 985 and J. S. Patterson, xe2x80x9c10 Years of Tamoxifen in Breast Cancerxe2x80x9d in Hormonal Manipulation of Cancer; Peptides, Growth Factors and New (Anti)steroidal Agents, Raven Press, New York (1987)).
Steroidal antiestrogens are described in European Patent Application 0 138 504. Antiestrogenic indole derivatives are already known from German Patent 32 32 968, from J. Med. Chem. 1983, 26, 113; J. Med. Chem., 1984, 27, 1439, Eur. J. Cancer. Clin. Oncol. 1985, 21, 531 and Cancer Treatment Reviews 1984, 11, 147 as well as N-aminoalkylindoles, which in addition to pronounced antiestrogenic action exhibit only slight estrogenic activity, from European Patent Application 0 348 341.
Hydroxylated 2-phenylindoles, which are present in the form of diamine-platinum(II) complex compounds, are mentioned in German Laid-Open Specification 37 30 746.
A considerable number of the most widely varied compoundsxe2x80x94i.a., those of steroidal origin and those with a 2-phenylindole skeletonxe2x80x94that act as antiestrogens and/or suppress estrogen biosynthesis, are disclosed in WO 93/10741.
The compounds of general formula I according to this application are distinguished from the 2-phenylindoles that are already known by novel side chains on the nitrogen atom. This structural modification leads to especially high antiestrogenically active compounds, which have a very high affinity for the estradiol receptor and displace competitive 3H-17xcex2-estradiol from the receptor.
Here, mainly those compounds in which R10 and R11 together form a di-, tri- or tetramethylene bridge and especially an ethano bridge, i.e., benzo[a]carbazoles, are to be emphasized. In comparison to the analogous compounds, in which R10 is a methyl group and R11 is a hydrogen atom, the benzo[a]carbazoles according to general formula I are distinguished by an even higher affinity for the estrogen receptor and stronger tumor-inhibiting action.
The cytostatic activity of the new compounds (cell structure tests) is higher than the comparable 2-phenylindoles with an acid amide group in the side chain (EP-A 0348 341).
The IC50 values for the new compounds lie in the nanomolar range.
At the same time, these are, for the most part, particularly pure antiestrogens (no residual estrogenic action).
Estrogenic effects on the uteri of mice can no longer be demonstrated in vivo. The compounds have an inhibiting effect on the growth of hormone-dependent tumor cells; they especially inhibit the growth of estrogen-dependent human breast neoplasm cells (MCF-7).
The compounds according to the invention thus are suitable for treating estrogen-dependent diseases, for example, prostatic hyperplasia, breast cancer, endometrial carcinoma, anovulatory infertility and melanoma. In addition, they can be used for prophylaxis and treatment of osteoporosis (Black, L. J.; Sato, M.; Rowley, E. R.; Magee, D. E.; Bekele, A.; Williams, D. C.; Cullinan, G. J.; Bendele, R.; Kauffman, R. F.; Bensch, W. R.;
Frolik, C. A.; Termine, J. D. and Bruant, H. U.: Raloxifene [LY 139481 HCl] Prevents Bone Loss and Reduces Serum Cholesterol without Causing Uterine Hypertrophy in Ovariectomized Rats; J. Clin. Invest. 93: 63-69, 1994).
The following pharmacological tests show the action of the compounds according to the invention.
Table 1 shows an overview of the tested compounds of general formula I and their relative binding affinities (RBA*) for the estrogen receptor consisting of calf uteri, compared to 17xcex2-estradiol=100.
The test arrangement is described in Cancer Treatment Reviews 1984, 11, 147.
Table 1 indicates especially the bridge of skeleton atoms 3 and 2xe2x80x2, which with an ethano bridge (carbazoles) again ensures significantly increased activities in comparison to the phenylindoles.
Table 2 shows the results of the studies on the cytostatic activity of selected compounds in comparison to tamoxifen.
A strong inhibition of cell growth was found with hormone-sensitive human MCF-7 breast cancer cells.
Compound no. 3 does not show any estrogenic action on the uterus of infantile mice; at a dose of 35 mg/kg, the dry weight of the uterus still lies below the control level. At 10 mg/kg, the action of estrogen (0.4 xcexcg/animal) is completely cancelled out. For compounds nos. 3 and 11, virtually identical results were obtained. The dose/animal was administered s.c., dissolved in olive oil, on three successive days. The dry weight of the uterus [mg]/body weight [g]xc3x97100 was determined 24 hours after the last injection. This test is described in detail in Cancer Treatment Reviews, 1984, 11, 147 and J. Med. Chem., 1984, 27, 1439.
The invention also relates to pharmaceutical preparations that contain at least one compound of general formula I and the use of this compound for treating estrogen-dependent diseases and tumors.
The compounds according to the invention are suitable for the production of pharmaceutical compositions and preparations. The pharmaceutical compositions or pharmaceutical agents contain as active ingredient one or more of the compounds according to the invention, optionally mixed with other pharmacologically or pharmaceutically active substances. The production of the pharmaceutical agents is carried out in a known way, whereby the known and commonly used pharmaceutical adjuvants as well as other commonly used vehicles and diluents can be used.
As such vehicles and adjuvants, for example, those are suitable that are recommended or indicated in the following bibliographic references as adjuvants for pharmaceutics, cosmetics and related fields: Ullmans Encyklopxc3xa4die der technischen Chemie [Ullman""s Encyclopedia of Technical Chemistry], Volume 4 (1953), pages 1 to 39; Journal of Pharmaceutical Sciences, Volume 52 (1963), pages 918 ff; H. v. Czetsch-Lindenwald, Hilfsstoffe fxc3xcr Pharmazie und angrenzende Gebiete [Adjuvants for Pharmaceutics and Related Fields]; Pharm. Ind. No. 2, 1961, pages 72 ff.; Dr. H. P. Fiedler, Lexikon der Hilfsstoffe fxc3xcr Pharmazie, Kosmetik und angrenzende Gebiete [Dictionary of Adjuvants for Pharmaceutics, Cosmetics and Related Fields], Cantor Kg. Aulendorf in Wxc3xcrttemberg 1971.
The compounds can be administered orally or parenterally, for example intraperitoneally, intramuscularly, subcutaneously or percutaneously. The compounds can also be implanted in the tissue. The amount of compounds to be administered varies within a wide range and can cover any effective amount. On the basis of the condition to be treated and the type of administration, the amount of compound that is administered is 0.01-20 mg/kg of body weight, preferably 0.1-5 mg/kg of body weight per day.
For oral administration, capsules, pills, tablets, coated tablets, etc. are suitable. In addition to the active ingredient, the dosage units can contain a pharmaceutically compatible vehicle, such as, for example, starch, sugar, sorbitol, gelatin, lubricant, silicic acid, talc, etc. The individual dosage units for oral administration can contain, for example, 10 to 100 mg of active ingredient.
For parenteral administration, the active ingredients can be dissolved or suspended in a physiologically compatible diluent. As a diluent, very frequently oils are used with or without the addition of a solubilizer, a surfactant, a suspending agent or emulsifying agent. Examples of oils that are used are olive oil, peanut oil, cottonseed oil, soybean oil, castor oil and sesame oil.
The compounds can also be used in the form of a depot injection or an implant preparation, which can be formulated such that a delayed release of active ingredient is made possible.
As inert materials, implants can contain, for example, biodegradable polymers or synthetic silicones, such as, for example, silicone rubber. In addition, the active ingredients can be added to, for example, a patch for percutaneous administration.
The production of the compounds according to the invention is carried out as described in the examples. Compounds that are homologous to those in the examples are reproduced by an analogous procedure using corresponding homologous reagents.
The reaction diagram is shown in FIG. 1:
In general, the sulfur-containing side chain, which was obtained according to conventional methods, is
(i) introduced directly into the 5-methoxy-2-(4-methoxyphenyl)-3-methylindole by N-alkylation, and
(ii) the alkyl ether (especially methyl ether) is cleaved with, for example, boron tribromide.
Since the sulfoxides decompose under the conditions of ether cleavage, in this case first
(viii) the alkylether groups of 5-methoxy-2-(4-methoxyphenyl)-3-methylindole are cleaved and the phenolic hydroxy groups are protected with 3,4-dihydro-2H-pyran, and then
(ix) the sulfur-containing side chain is introduced by N-alkylation, and
(x) the protective groups are cleaved.
The synthesis of compounds can be carried out with a mixed-functional side chain by
(ii) N-alkylation of 5-methoxy-2-(4-methoxyphenyl)-3-methylindole with a corresponding xcex1,xcfx89-dibromoalkane, then
(v) substitution of the terminal halogen by a thiol group with the isoalkylthiouronium salt,
(vi) alkylation of thiol with the corresponding xcfx89-bromoalkanoylamide, and
(vii) ether cleavage.
The sulfonamides of general formula I are accessible by
(i) alkylation of 5-methoxy-2-(4-methoxyphenyl)-3-methylindole with the corresponding xcfx89-bromoalkanoylamide,
(iii) reduction of the carbonyl group with lithium aluminum hydride,
(iv) reaction of the amine that is obtained with the corresponding alkylsulfonyl chloride in the presence of a base, and
(vii) ether cleavage.
The radical xe2x80x94(CH2)mxe2x80x2, phenylene-Xxe2x80x94(CH2)nxe2x80x2xe2x80x94S(O)mR4 can be introduced by reaction of 5-methoxy-2-(4-methoxyphenyl)-3-methylindole with p-bromobenzoic acid esters (or p-bromomethyl-or p-bromoethylbenzoic acid esters) in the presence of CuO (Ullmann reaction) and creation of the side chain via the ester group according to known processes.
For X=NR6, a start can be made from the easily accessible 1-(p-nitrophenyl) derivatives, which are reduced to amine. The residual side chain is then introduced in a nucleophilic substitution reaction with halogen compounds, as they are also used for introducing the side chain directly on the indole-nitrogen. The phenol or thiophenol can be produced with diazonium salt, which then is suitable for obtaining the derivatives with X=O and X=S.
If this is ultimately to be a higher alkyl ether of general formula I, radicals R2 and R3 can be obtained as early as in the starting compound. A carbamoyl radical can be established at these points by deprotonation of the phenolic hydroxy groups and reaction with the corresponding carbamic acid chloride (chloroformic acid amides).
Other possible radicals R2 and R3 according to the invention can be obtained starting from the respective phenol according to familiar methods.
The bridged derivatives, in which R10+R11 represent a tri- or tetramethylene bridge, can be obtained analogously to the dihydrobenzocarbazoles by the Fischer-indole synthesis of substituted phenylhydrazines with a corresponding benzocyclohept-2-enone or benzocyclooct-2-enone. A double bond in conjugation with the phenyl ring can be introduced by benzyl halogenation, with, e.g., NBS, and dehydrohalogenation.